For years, extensive efforts have been expended in search of effective antiplaque agents from a wide variety of sources. Although selected antimicrobial and antiseptic chemicals have been incorporated into dentifrices, the incorporation of plant-derived antimicrobials into such products has only begun recently in the United States. We have developed methodology for screening, fractionating and identifying oral antimicrobials from natural plant sources and have identified nitidine, a benzophenanthridine alkaloid isolated from the roots of Zanthoxylum nitidum (ZN), that exhibits antimicrobial activity against oral cariogenic bacteria. The overall hypothesis underlying this research is that important compounds offering significant antimicrobial and antiplaque properties without corresponding mammalian toxicity can be isolated from plant sources. The Specific Aims of this study are, SA1: To delineate the biological activity of nitidine and its analogs. The antimicrobial activity of nitidine against a broad spectrum of oral bacteria and its effect on selected cariogenic determinants of mutans streptococci will be examined. Upon confirming the antimicrobial activity of nitidine, cytotoxicity tests will be carried out to ensure its safety for human applications. SA2: To investigate the specific mechanism of antimicrobial action of nitidine against MS cells. Our hypothesis is that nitidine may exert its antiplaque effect by interfering with cellular macromolecular synthesis of MS or by interfering with the cell surface glucan-binding protein (GHP) activity. The interaction of nitidine with GBP will be examined through binding studies, immunoblot assays and spectrophotometric studies. SA3: we will synthesize nitidine analogs and to perform structure-activity relationships (SAR) studies. This will elucidate the structural features required for the biological activity of nitidine; so to obtain a more effective compound that existing agents for future clinical application. These studies will be performed as a logical sequence that permits evaluation of effectiveness as an antimicrobial compound, and toxicity before proceeding to more detailed evaluation. The importance of this research lies not only in the possibility of developing therapeutic compounds based directly on nitidine or its analogs, but on the refinement of a methodology that will permit screening of other plant derived compounds for potential use as antiplaque agents.